ABSTRACT/PROJECTSUMMARY Ischemicmitralregurgitation(IMR)isrefluxofbloodthroughthemitralvalve,developinginpatientssurvivinga myocardial infarction or chronic ischemic heart disease. 2.7 million Americans suffer from this condition and progressively develop congestive heart failure. Their hospitalization rates are higher and they present with significantriskofsuddendeath.TimelycorrectionofIMRcanhaltadverseventricularremodeling,butcurrent techniquestorepairIMRrequireopen-heartsurgery,ariskyprocedureinthesepatients.Severaltranscatheter strategies are in development, but all of them have demonstrated poor outcomes with significant remnant regurgitation or repair failure due to procedural complexity. We hypothesized that the most effective and durable technique to correct IMR is by extending the native leaflet lengths at the site of the regurgitation, restoring systolic leaflet edge parallelization, so that coaptation is restored and regurgitation is effectively eliminated. We developed a novel, flexible;? nitinol implant covered with expanded polytetrafluoroethylene, which when deployed on the anterior or posterior mitral valve leaflet extends the leaflet shelf and restores leaflet coaptation. The device integrates into the native leaflet with tissue encapsulation over 4-6 weeks, and theendothelializedtissuepermanentlyaddstothenativeleafletlengthforIMRcorrection.Strongpreliminary datasupportingthefeasibilityandsafetyofthisconcepthavebeengeneratedinexvivoandswinemodels.In thisR01application,weproposetoadvancethisconceptfurther,withafocusonoptimizingthedevicedesign tobestrestorevalvefunctionandpreservevalvemechanics.Threeaimsareproposed-(Aim1)Optimizethe devicefeaturestoachievebestIMRreductionandhighestleafletcoaptation,whilepreservingthenativevalve mechanics and fluid dynamics;? (Aim 2) investigate the durability of the device in correcting IMR in a progressively remodeling LV, investigate chronic device healing and tissue remodeling, and measure the thrombotic potential of the device in swine;? and (Aim 3) develop a trans-septal delivery catheter for image guided deployment of the device on the mitral valve, and assess the safety and efficacy of this procedure in swine.Wehaveassembledacollaborative,multidisciplinaryteamwithexperienceinbiomedicaldevicedesign &engineering,computationaltissueandfluidmechanics,animalmodelsandimaging,andclinicalexperience intranscathetervalvetherapies,inanenvironmentwithahistoryofinnovativecardiacresearch.Thereishigh potential for clinical translation of this technology, and the proposed work will optimize the technology and mitigate the failure modes & risks. Completion of the proposed aims will result in a significantly better therapeutic option to repair ischemic mitral regurgitation, which is a highly translational end-point and will addressasignificantunmetclinicalneed.